Important Compound Classes
Title
Substituted Naphthyridinone Compounds Useful as T Cell Activators
Patent Application Number
WO 2020/006018 Al
Publication Date
January 2, 2020
Priority Application
US 62/690,439 and US 62/840,459
Priority Date
June 27, 2018; April 30, 2019
Inventors
Velaparthi, U.; Chupak, L. S.; Darne, C. P.; Ding, M.; Gentles, R. G.; Huang, Y.; Kamble, M. N. R.; Martin, S. W.; Mannoori, R.; Mcdonald, I. M. Olson, R. E.; Rahaman, H.; Jalagam, P. R.; Roy, S.; Tonukunuru, G.; Velaiah, S.; Warrier, J. S.; Zheng, X.; Tokarski, J. S.; Dasgupta, B.; Reddy, K. R.; Raja, T.
Assignee Company
Bristol-Myers Squibb Company; Route 206 and Province Line Road, Princeton, New Jersey 08543 (USA).
Disease Area
Proliferative disorders such as cancer, and viral infections
Biological Target
Diacylglycerol kinases (DGKs)
Summary
The invention in this patent application relates to naphthyridinone derivatives represented generally by formula I. These compounds are inhibitors of DGKα and/or DGKζ and can activate T cells, promote T cell proliferation, and/or exhibit antitumor activity. The compounds may potentially be useful for the treatment of proliferative disorders, such as cancer, as well as viral infections.
Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system. The human immune system is divided into two components, the innate and the adaptive immune systems. The innate system is the first line of defense against pathogens via an automatic, nonspecific, and fast response mechanism. The adaptive immune system, also called acquired immunity, is a slow-response mechanism that is activated by exposure to pathogens and uses specific antigens to strategically mount an immune response. The adaptive system recognizes the threat and designs specific immune cells to attack the threat. Additionally, it saves immunological memory to enhance the immune response to defend against similar future attacks. The active components of the adaptive immune system that counter harmful antigens are two kinds of white blood cells, the T and B lymphocytes. Studies have indicated that these white cells are potentially powerful anticancer agents that could respond to multiple tumor antigens with a broad capacity and high specificity. Thus, the adaptive immune system combines considerable plasticity and the advantage of a memory component. Harnessing these adaptive immune system attributes successfully is the basis of immunotherapy which is a unique approach to cancer treatment.
Researchers have observed response by the endogenous immune system against cancer cells in preclinical models, but the response is usually weak and ineffective. Cancer cells avoid recognition by the immune system through expressing nonmutated or “self” antigens. Thus, while T-cells and antibodies can recognize these self-antigens, the response by the immune system against them is ineffective due to their deceiving nature. This may also explain the difficulties in developing immunizations against cancer. There are several additional mechanisms that contribute to subverting antitumor immunity including the following:
dysfunctional T-cell signaling
suppressive regulatory T-cells
endogenous “immune checkpoints” that minimize the intensity of the adaptive immune responses against tumors.
Diacylglycerol kinases (DGKs) are members
of a lipid kinase family.
There are 10 known Mammalian DGK isoforms grouped based on their regulatory
domains into 5 subtypes. DGKs contribute to the control of the immune
system response through catalyzing the conversion of the second messenger
lipid diacylglycerol (DAG) to phosphatidic acid (PA).
This conversion simultaneously constrains DAG signaling while promoting PA signaling. Studies have determined a key role for DAG signaling in T cell development and function. Consequently, terminating DAG signaling causes the termination of T cell functions propagated through the T-cell receptor (TCR) signaling pathway. Thus, DGKs serve as intracellular checkpoints to down-modulate the intensity of the adaptive immune responses against tumor cells. Therefore, the inhibition of DGKs can potentially help maintain higher levels of DAG, and this, in turn, is expected to enhance T cell signaling pathways and T cell activation. More specific evidence came from studies using knockout mouse models of two DGK isoforms, diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ) that show a hyper-responsive T cell phenotype and improved antitumor immune activity. Furthermore, DGKα was found to be overexpressed in tumor infiltrating lymphocytes isolated from human renal cell carcinoma patients which resulted in inhibited T cell function. These data show that the selective inhibition of DGKα and/or DGKζ is a promising and viable therapeutic target for the development of an immunotherapy treatment for cancer.
There is currently an unmet need for compounds that act as inhibitors of one or both of DGKα and DGKζ.
The ideal inhibitors of DGKα and/or DGKζ should possess some or all of the following properties:
selective for DGKα and/or DGKζ over other diacylglycerol kinases, protein kinases, and/or other lipid kinases
safe and effective in restoring T cell activation
capable of lowering antigen threshold
capable of enhancing antitumor functionality
can overcome the suppressive effects of one or more endogenous immune checkpoints, such as programmed death-1 (PD-1), lymphocyte activation gene (LAG), and transforming growth factor-β (TGFβ).
The compounds of formula I in this patent application are selective inhibitors of one or both of DGKα and DGKζ with selectivity over other diacylglycerol kinases, protein kinases, and/or other lipid kinases. These compounds possess desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability and may potentially provide useful treatment for proliferative disorders, such as cancer, as well as viral infections.
Key Structures
The inventors described the structures
and methods of synthesis of 1454 examples of formula I including the
following representative examples:
Biological Assay
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1.
In vitro DGK Inhibition Assays (DGKα: and DGKζ LIPGLO assays)
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2.
Raji CD4 T cell IL2 Assay
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3.
Cell Titer-Glo CD8 T Cell Proliferation Assay
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4.
DGK APl-Reporter Assay
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5.
Murine Cytotoxic T Lymphocyte Assay
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6.
PHA Proliferation Assay
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7.
Human CD8 T cells IFN-γ Assay
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8.
Human CD8 T cells pERK Assay
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9.
Human Whole Blood IFN-γ Assay
Biological Data
The biological data obtained from testing
the above representative examples using some of the assays are summarized
in the following table
Recent Review Articles
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1.
Sadreddini S.; Baradaran B.; Aghebati-Maleki A.; Sadreddini S.; Shanehbandi D.; Fotouhi A.; Aghebati-Maleki L.. J. Cell. Physiol. 2019, 234 ( (6), ), 8541–8549..
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2.
Merida I.; Torres-Ayuso P.; Avila-Flores A.; Arranz-Nicolas J.; Andrada E.; Tello-Lafoz M.; Liebana R.; Arcos R.. Adv. Biol. Regul. 2017, 63, 22–31..
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3.
Merida I.; Andrada E.; Gharbi S. I.; Avila-Flores A.. Sci. Signal 2015, 8, (374), 1–12..
The author declares no competing financial interest.